Multiple lines of evidence suggests that estrogen(E) directly modulates angiogenesis. Under physiologic conditions, angiogenesis is routinely observed in the uterus in association with fluctuations in the levels of circulating estradiol(E2) and other sex steroids. In pathologic circumstances, such as breast cancer, a clear association between E, estrogen receptor (ER) expression, angiogenic activity and tumor invasiveness has been drawn. Despite These consistent observations, the mechanisms by which E regulates angiogenesis under physiologic and pathologic circumstances have not been defined. Prior studies indicate that hematopoietic stem cells (HSCs) and endothelial progenitor cells (EPCs) are derived from a common precursor, the hemangioblast. Based on these studies our laboratory investigated the possibilities that stem cells derived from peripheral blood could differentiation into endothelial cells (EC) and thereby participate in angiogenesis. Additional preliminary marrow (BM) derived EPC and the incorporation of these precursors into foci of vasculogenesis. Accordingly, the proposed studies are designed to clarify and extend these preliminary findings. These studies are organized to examine hypotheses the following specific aims:
SPECIFIC AIM 1 : Define Modulation of EPC kinetics y Estrogen;
SPECIFIC AIM 2 : Define the Role of Estrogen Receptor in Estrogen-induced, EPC-mediated Neovascularization;
SPECIFIC AIM 3 : Investigate Certain Mechanisms which Mediate Estrogen-Induced, EPC-Derived Neovascularization. Our preliminary data provide evidence that E2 induced neovascularization is the result, at least in part, of vasculogenesis resulting from recruitment and incorporation of BM derived EPC. These data are in contrast to the conventional paradigm of angiogenesis (i.e. sprouts derived from pre-existing, fully differentiated EC) which has been assumed to account for E2 induced blood vessel formation. The study of neovascularization in the model for E2 induction will provide the opportunity to examine these mechanisms in a physiologically relevant context and thereby discern certain fundamental mechanisms responsible for post-natal neovascularization.
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